Huntington's disease (HD) is a fatal and untreatable hereditary disorder that produces progressive motor dysfunction and mental deterioration. The goals of this study are to understand the factors that determine the susceptibility of specific neuronal populations to degeneration in HD and to test the hypothesis that the synaptic terminations of non-limbic corticostriatal axons are the initial site of degeneration in HD. The specific aims of this study are to define the morphology and neurochemical characteristics of neuronal populations that are affected or spared, to determine the regional topography of striatal degeneration, and to examine the relationship of extrastriatal sites to striatal pathology in HD. The specific aims will be achieved by using immunocytochemical, enzyme histochemical, and section-Golgi methods to examine postmortem human brain tissue. Preliminary studies showed that NADPH diaphorase and, to a lesser extent, acetylcholinesterase (AChE) neurons are preserved in HD striatum. The extent of preservation of other aspiny neurons, such as those that contain vasoactive intestinal polypeptide, cholecystokinin, GABA, and substance P, will be determined in different grades of HD. Spiny neurons, that contain enkephalins, dynorphin, GABA, calcium-binding protein, and substance P; and receive the bulk of corticostriatal terminals, will be assessed for evidence of degeneration in early stages of HD. Markers of striatal matrix, such as calcium-binding protein and cytochrome oxidase; and striatal patches, such as neurotensin, will be examined to determine if they confirm the sparing of low AChE patches found in HD. Substance P and AChE neurons located in patches will be compared to those in matrix to determine if neuronal location contributes to the extent of neuronal degeneration in HD striatum. Nigrostriatal and corticostriatal projection systems will be studied for evidence of retrograde degeneration. Defining the pathological basis of HD will permit the accurate assessment of animal models, improve the accuracy of clinical diagnosis, and provide new insights into the etiology and pathogenesis of HD.